JPH0662584B2 - Novel hydantoin derivative and lipid lowering agent containing the compound - Google Patents
Novel hydantoin derivative and lipid lowering agent containing the compoundInfo
- Publication number
- JPH0662584B2 JPH0662584B2 JP60287097A JP28709785A JPH0662584B2 JP H0662584 B2 JPH0662584 B2 JP H0662584B2 JP 60287097 A JP60287097 A JP 60287097A JP 28709785 A JP28709785 A JP 28709785A JP H0662584 B2 JPH0662584 B2 JP H0662584B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- hydantoin
- hydroxy
- present
- melting point
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001469 hydantoins Chemical class 0.000 title claims description 10
- 239000003524 antilipemic agent Substances 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 title description 33
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 28
- 229940091173 hydantoin Drugs 0.000 description 24
- 238000001819 mass spectrum Methods 0.000 description 19
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- -1 methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, s-butoxy, t-butoxy Chemical group 0.000 description 12
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 235000021588 free fatty acids Nutrition 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 4
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- XERNRFRHTSHCDS-UHFFFAOYSA-N 1-benzyl-5-hydroxyimidazolidine-2,4-dione Chemical compound O=C1NC(=O)C(O)N1CC1=CC=CC=C1 XERNRFRHTSHCDS-UHFFFAOYSA-N 0.000 description 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 2
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 description 2
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 2
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- RJNJWHFSKNJCTB-UHFFFAOYSA-N benzylurea Chemical compound NC(=O)NCC1=CC=CC=C1 RJNJWHFSKNJCTB-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 229940066842 petrolatum Drugs 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- UDCOPDXTLYPSTO-UHFFFAOYSA-N 1-benzyl-1-nitrourea Chemical compound NC(=O)N([N+]([O-])=O)CC1=CC=CC=C1 UDCOPDXTLYPSTO-UHFFFAOYSA-N 0.000 description 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- GHLYGGIKYFLYTH-UHFFFAOYSA-N 3-methylbenzenesulfonic acid;hydrate Chemical compound O.CC1=CC=CC(S(O)(=O)=O)=C1 GHLYGGIKYFLYTH-UHFFFAOYSA-N 0.000 description 1
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- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 208000018914 glucose metabolism disease Diseases 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 208000009928 nephrosis Diseases 0.000 description 1
- 231100001027 nephrosis Toxicity 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- MOOYVEVEDVVKGD-UHFFFAOYSA-N oxaldehydic acid;hydrate Chemical compound O.OC(=O)C=O MOOYVEVEDVVKGD-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は新規ヒダントイン誘導体及びその薬学的に許容
しうる塩、並びに該化合物を有効成分として含有する脂
質低下剤に関する。TECHNICAL FIELD The present invention relates to a novel hydantoin derivative and a pharmaceutically acceptable salt thereof, and a lipid lowering agent containing the compound as an active ingredient.
（従来の技術） 血中にはトリグリセライド、コレステロール、リン脂
質、遊離脂肪酸等の脂質が存在するが、それら脂質の異
常な増加やアンバランスなどにより種々の病的状態をき
たす。即ち、高脂血症は動脈硬化形成の原因となるばか
りでなく、糖代謝異常、虚血性心疾患等の諸症状を呈す
る。(Prior Art) There are lipids such as triglyceride, cholesterol, phospholipids and free fatty acids in the blood, which cause various pathological conditions due to abnormal increase or imbalance of these lipids. That is, hyperlipidemia not only causes arteriosclerosis formation, but also presents various symptoms such as abnormal glucose metabolism and ischemic heart disease.
本発明者らは、有効で安全な脂質低下作用を有する化合
物を探究するうち、本発明ヒダントイン誘導体及びその
薬学的に許容しうる塩が優れた脂質低下作用を有し、し
かも低毒性で極めて安全性の高いものであることを見出
し本発明を完成した。The present inventors have been searching for a compound having an effective and safe lipid-lowering action, and the hydantoin derivative of the present invention and a pharmaceutically acceptable salt thereof have an excellent lipid-lowering action, and have low toxicity and are extremely safe. The present invention has been completed by finding out that it has high properties.
（発明が解決しようとする問題点） 本発明の目的は、低毒性で優れた脂質低下作用を有し、
経口投与可能な新規ヒダントイン誘導体及びその薬学的
に許容しうる塩、並びに該化合物を有効成分として含有
す医薬組成物を提供することにある。(Problems to be Solved by the Invention) An object of the present invention is to have a low toxicity and an excellent lipid-lowering effect,
It is an object of the present invention to provide a novel hydantoin derivative which can be orally administered, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient.
（問題点を解決するための手段） 本発明化合物は下記一般式（Ｉ）で表される新規ヒダン
トイン誘導体である。(Means for Solving Problems) The compound of the present invention is a novel hydantoin derivative represented by the following general formula (I).
（式中、Ｒ１及びＲ２は同一若しくは異なって水素、ハ
ロゲン、ニトロ基、低級アルキル基又は低級アルコキシ
基を表す。） 上記一般式（Ｉ）においてＲ１及びＲ２はそれぞれ同一
若しくは異なって水素、弗素、塩素、臭素等のハロゲ
ン、ニトロ基、低級アルキル基、好ましくはメチル、エ
チル、プロピル、ｉ−プロピル、ブチル、ｉ−ブチル、
ｓ−ブチル、ｔ−ブチル等の直鎖又は分枝状の炭素数１
乃至４の低級アルキル基、又は、低級アルコキシ基、好
ましくはメトキシ、エトキシ、プロポキシ、ｉ−プロポ
キシ、ブトキシ、ｉ−ブトキシ、ｓ−ブトキシ、ｔ−ブ
トキシ等の直鎖又は分枝状の炭素数１乃至４の低級アル
コキシ基を表す。 (In the formula, R 1 and R 2 are the same or different and each represents hydrogen, halogen, a nitro group, a lower alkyl group or a lower alkoxy group.) In the above general formula (I), R 1 and R 2 are the same or different. Hydrogen, halogen such as fluorine, chlorine and bromine, nitro group, lower alkyl group, preferably methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
Linear or branched carbon number 1 such as s-butyl and t-butyl
To 4 lower alkyl groups or lower alkoxy groups, preferably linear or branched carbon number 1 such as methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, s-butoxy, t-butoxy. 4 represents a lower alkoxy group.
本発明化合物中特に好ましい化合物は以下の通りであ
る。Among the compounds of the present invention, particularly preferable compounds are as follows.
・５−ヒドロキシ−１−ベンジルヒダントイン ・５−ヒドロキシ−１−（２−フルオロベンジル）ヒダ
ントイン ・５−ヒドロキシ−１−（３−フルオロベンジル）ヒダ
ントイン ・５−ヒドロキシ−１−（４−フルオロベンジル）ヒダ
ントイン ・５−ヒドロキシ−１−（２−クロロベンジル）ヒダン
トイン ・５−ヒドロキシ−１−（４−クロロベンジル）ヒダン
トイン ・５−ヒドロキシ−１−（４−ブロモベンジル）ヒダン
トイン ・５−ヒドロキシ−１−（３−ニトロベンジル）ヒダン
トイン ・５−ヒドロキシ−１−（４−ニトロベンジル）ヒダン
トイン ・５−ヒドロキシ−１−（２−メチルベンジル）ヒダン
トイン ・５−ヒドロキシ−１−（３−メチルベンジル）ヒダン
トイン ・５−ヒドロキシ−１−（４−メチルベンジル）ヒダン
トイン ・５−ヒドロキシ−１−（３−メトキシベンジル）ヒダ
ントイン ・５−ヒドロキシ−１−（４−メトキシベンジル）ヒダ
ントイン ・５−ヒドロキシ−１−（3,4−ジメトキシベンジル）
ヒダントイン ・５−ヒドロキシ−１−（3,4−ジクロロベンジル）ヒ
ダントイン 本発明ヒダントイン誘導体は、前記一般式（Ｉ）で表さ
れる化合物の薬学的に許容しうる塩を包含し、例えば、
ナトリウム、カリウム等のアルカリ金属、カルシウム、
マグネシウム等のアルカリ土類金属、その他アルミニウ
ム等との金属塩、アンモニア、有機アミン等との塩が挙
げられる。5-hydroxy-1-benzylhydantoin 5-hydroxy-1- (2-fluorobenzyl) hydantoin 5-hydroxy-1- (3-fluorobenzyl) hydantoin 5-hydroxy-1- (4-fluorobenzyl) Hydantoin 5-hydroxy-1- (2-chlorobenzyl) hydantoin 5-hydroxy-1- (4-chlorobenzyl) hydantoin 5-hydroxy-1- (4-bromobenzyl) hydantoin 5-hydroxy-1- (3-Nitrobenzyl) hydantoin-5-hydroxy-1- (4-nitrobenzyl) hydantoin-5-hydroxy-1- (2-methylbenzyl) hydantoin5-hydroxy-1- (3-methylbenzyl) hydantoin 5-hydroxy-1- (4-methylbenzyl) hydan In-5-hydroxy-1- (3-methoxybenzyl) hydantoin, 5-hydroxy-1- (4-methoxybenzyl) hydantoin, 5-hydroxy-1- (3,4-dimethoxybenzyl)
Hydantoin-5-hydroxy-1- (3,4-dichlorobenzyl) hydantoin The hydantoin derivative of the present invention includes a pharmaceutically acceptable salt of the compound represented by the general formula (I).
Alkali metals such as sodium and potassium, calcium,
Examples thereof include alkaline earth metals such as magnesium, metal salts with other aluminum and the like, salts with ammonia, organic amines and the like.
こられの塩は公知の方法により遊離の本発明ヒダントイ
ン誘導体より製造でき、或いは相互に変換することがで
きる。These salts can be prepared from the free hydantoin derivative of the present invention by a known method, or can be converted into each other.
又、本発明化合物において光学異性体が存在する場合に
は、本発明はそのｄ−体、ｄ−体及び−体のいずれ
をも包含する。Further, when the compound of the present invention has an optical isomer, the present invention includes any of the d-form, d-form and-form thereof.
次に、本発明化合物の製造方法の一例を述べる。Next, an example of the method for producing the compound of the present invention will be described.
先ず、グリオキシル酸に通常のエステル化反応を行う。
即ち、グリオキシル酸又はその水和物とベンジルアルコ
ール等のアルコール類をベンゼン、トルエン、キシレ
ン、四塩化炭素等のアプロティック溶媒中、ｐ−トルエ
ンスルホン酸、カンファースルホン酸等の有機酸触媒存
在下、数時間乃至一日間室温乃至加熱して若しくは還流
させる。生じたグリオキシル酸エステル又はグリオキシ
ル酸エステルヘミアセタールを単離することなく或いは
精製した後、適当な溶媒中、例えば水、酢酸、ブタノー
ル等のアルコール或いはこれらの混合溶媒中、室温乃至
還流下１時間乃至数日間、Ｎ−ベンジル尿素、Ｎ−ハロ
ゲンベンジル尿素、Ｎ−ニトロベンジル尿素、Ｎ−アル
キルベンジル尿素、Ｎ−アルコキシベンジル尿素等のＮ
−置換尿素と反応させて一般式（Ｉ）で表される本発明
化合物を得ることができる。First, a general esterification reaction is performed on glyoxylic acid.
That is, glyoxylic acid or a hydrate thereof and alcohols such as benzyl alcohol in an aprotic solvent such as benzene, toluene, xylene and carbon tetrachloride in the presence of an organic acid catalyst such as p-toluenesulfonic acid and camphorsulfonic acid, Allow to be at room temperature to heat or reflux for a few hours to a day. The resulting glyoxylic acid ester or glyoxylic acid ester hemiacetal is purified without isolation or in a suitable solvent, for example, water, acetic acid, alcohol such as butanol, or a mixed solvent thereof, at room temperature or under reflux for 1 hour to For several days, N-benzylurea, N-halogenbenzylurea, N-nitrobenzylurea, N-alkylbenzylurea, N-alkoxybenzylurea, etc.
-The compound of the present invention represented by the general formula (I) can be obtained by reacting with a substituted urea.
得られた本発明化合物は、蒸留、クロマトグラフィー、
再結晶等の通常の手段により精製し、融点、ＩＲ、ＮＭ
Ｒ、マススペクトル（ＭＳ）等により同定を行った。The obtained compound of the present invention is subjected to distillation, chromatography,
Purified by ordinary means such as recrystallization, melting point, IR, NM
Identification was performed by R, mass spectrum (MS) and the like.
（実施例） 以下に、実施例により本発明化合物の製造例を示す。(Example) Below, the production example of the compound of this invention is shown by an Example.
実施例１． (1)グリオキシル酸・１水和物116ｇをディーンスターク
の装置を付した２のフラスコに入れ、ベンジルアルコ
ール500ｍ、トルエン800ｍ及びｐ−トルエンスルホ
ン酸・１水和物0.5ｇを加え２時間還流した。トルエン
を溜去した後、グリオキシル酸ベンジルエステルベンジ
ルエミアセタールｇを減圧蒸溜により融点107-110℃
（１mmHg）の溜分として集めた。Example 1. (1) 116 g of glyoxylic acid monohydrate was placed in a second flask equipped with a Dean-Stark apparatus, benzyl alcohol 500 m, toluene 800 m and p-toluenesulfonic acid monohydrate 0.5 g were added and refluxed for 2 hours. . After distilling off toluene, glyoxylic acid benzyl ester benzyl emiacetal g was distilled under reduced pressure to give a melting point of 107-110 ° C.
It was collected as a fraction of (1 mmHg).
収率：67.7％ (2)グリオキシル酸ベンジルエステルベンジルヘミアセ
タール19.1ｇを80％酢酸に溶かして油浴上で70℃に加熱
し、ここに80％酢酸に溶かしたＮ−ベンジル尿素8.8ｇ
を加えた後、1.5時間加熱還流した。反応終了後、減圧
下に酢酸を溜去し、トルエンを加え再び濃縮する操作を
繰り返して残存する酢酸をできる限り除去した。シリカ
ゲルカラムクロマトグラフィーで精製後、クロロホルム
で再結晶して５−ヒドロキシ−１−ベンジルヒダントイ
ン（化合物１）6.7ｇを得た。Yield: 67.7% (2) Glyoxylic acid benzyl ester Benzyl hemiacetal 19.1 g was dissolved in 80% acetic acid and heated to 70 ° C. on an oil bath, where 8.8 g of N-benzylurea dissolved in 80% acetic acid was added.
After adding, the mixture was heated under reflux for 1.5 hours. After completion of the reaction, acetic acid was distilled off under reduced pressure, toluene was added and the operation of concentration was repeated again to remove residual acetic acid as much as possible. After purification by silica gel column chromatography, it was recrystallized from chloroform to obtain 6.7 g of 5-hydroxy-1-benzylhydantoin (Compound 1).
収率：55.4％ 融点：137−139℃ ＩＲ（KBr）：3180，1735，1710，1125，705cm-1 ＮＭＲ（DMSO-d6）：δ＝4.23（d,1H,J＝16.0Hz），
4.58（d,1H,J＝16.0Hz），4.94（d,1H,J＝8.8Hz），7.0
2（d,1H,J＝8.8Hz），7.20-7.40（m,5H），10.89（br.
s,1H) ＭＳ（m/z）：207（Ｍ＋），132，106，91，65同様に
して以下の化合物を得た。Yield: 55.4% Melting point: 137-139 ° C IR (KBr): 3180, 1735, 1710, 1125, 705 cm -1 NMR (DMSO-d 6 ): δ = 4.23 (d, 1H, J = 16.0Hz),
4.58 (d, 1H, J = 16.0Hz), 4.94 (d, 1H, J = 8.8Hz), 7.0
2 (d, 1H, J = 8.8Hz), 7.20-7.40 (m, 5H), 10.89 (br.
s, 1H) MS (m / z): 207 (M + ), 132, 106, 91, 65 The following compounds were obtained in the same manner.
５−ヒドロキシ−１−（２−フルオロベンジル）ヒダン
トイン （化合物２） 収率：47.6％ 融点：141.5−143.5℃ ＩＲ（KBr）：3400，3320，3050，17801710，1580cm
-1 ＮＭＲ（DMSO-d6）：δ＝4.36（d,1H,J＝16.0Hz），
4.54（d,1H,J＝16.0Hz），4.97（d,1H,J＝8.8Hz），7.0
1（d,1H,J＝8.8Hz），7.14-7.40（m,4H），10.93（s,1
H) ＭＳ（m/z）：224（Ｍ＋），150，124，109，95，8
3，72，57，44，29 ５−ヒドロキシ−１−（３−フロオロベンジル）ヒダン
トイン （化合物３） 収率：49.1％ 融点：128−129℃ ＩＲ（KBr）：3400，3200，1760，1705，1590cm-1 ＮＭＲ（DMSO-d6）：δ＝4.30（d,1H,J＝16.4Hz），
4.52（d,1H,J＝16.4Hz），5.01（d,1H,J＝8.8Hz），7.0
2（d,1H,J＝8.8Hz），7.05-7.39（m,4H），10.92（s,1
H) ＭＳ（m/z）：224（Ｍ＋），150，124，109，95，8
3，72，57，44，29 ５−ヒドロキシ−１−（４−フロオロベンジル）ヒダン
トイン （化合物４） 収率：50.6％ 融点：181−182℃ ＩＲ（KBr）：3400，3280，1780，1710，1600cm-1 ＮＭＲ（DMSO-d6）：δ＝4.24（d,1H,J＝15.6Hz），
4.51（d,1H,J＝15.6Hz），4.96（d,1H,J＝8.8Hz），7.0
1（d,1H,J＝8.8Hz），7.12-7.35（m,4H），10.90（s,1
H) ＭＳ（m/z）：224（Ｍ＋），150，124，109，95，8
3，72，57，44，29 ５−ヒドロキシ−１−（４−クロロベンジル）ヒダント
イン （化合物５） 収率：36.4％ 融点：130−133℃ ＩＲ（KBr）：3240，3150，3030，1760，1700cm-1 ＮＭＲ（DMSO-d6）：δ＝4.42（d,1H,J＝16.4Hz），
4.53（d,1H,J＝16.4Hz），5.02（d,1H,J＝8.8Hz），7.0
2（d,1H,J＝8.8Hz），7.30-7.46（m,4H），10.98（s,1
H) ＭＳ（m/z）：224（Ｍ＋），205，166，140，125，9
9，89，77，72，44，29 ５−ヒドロキシ−１−（４−クロロベンジル）ヒダント
イン （化合物６） 収率：39.5％ 融点：150.5−152℃ ＩＲ（KBr）：3460，3160，3030，1780，1705cm-1 ＮＭＲ（DMSO-d6）：δ＝4.26（d,1H,J＝16.0Hz），
4.49（d,1H,J＝16.0Hz），4.97（d,1H,J＝8.4Hz），7.0
2（d,1H,J＝8.4Hz），7.32（d,2H,J＝8.4Hz），7.38（d
d,2H,J1＝2.0Hz,J2＝8.4Hz），10.91（s,1H) ＭＳ（m/z）：240（Ｍ＋），166，140，125，111，9
9，89，77，72，63，44，29 ５−ヒドロキシ−１−（４−ブロモベンジル）ヒダント
イン （化合物７） 収率：39.2％ 融点：168.5−169.5℃ ＩＲ（KBr）：3470，3160，3030，1780，1705，1590c
m-1 ＮＭＲ（DMSO-d6）：δ＝4.24（d,1H,J＝16.0Hz），
4.47（d,1H,J＝16.0Hz），4.98（d,1H,J＝8.4Hz），7.0
1（d,1H,J＝8.4Hz），7.26（d,2H,J＝8.4Hz），7.51（d
t,2H,J1＝2.0Hz,J2＝8.4Hz），10.91（s,1H) ＭＳ（m/z）：284（Ｍ＋），210，184，169，90，8
9，77，72，63，50，39，29 ５−ヒドロキシ−１−（３−ニトロベンジル）ヒダント
イン （化合物８） 収率：47.8％ 融点：161−163℃ ＩＲ（KBr）：3375，3200，3080，1755，1720，1540c
m-1 ＮＭＲ（DMSO-d6）：δ＝4.48（d,1H,J＝15.6Hz），
4.58（d,1H,J＝15.6Hz），5.06（d,1H,J＝8.8Hz），7.0
5（d,1H,J＝8.8Hz），7.63（dd,1H,J1＝8.0Hz,J2＝8.0H
z），7.77（d,1H,J＝8.0Hz），8.12（d,1H,J＝8.0H
z），8.17（s,1H)，10.96（s,1H) ＭＳ（m/z）：251（Ｍ＋），234，163，161，151，13
6，105，90，89，77，63，51，50，39，30 ５−ヒドロキシ−１−（４−ニトロベンジル）ヒダント
イン （化合物９） 収率：51.0％ 融点：171−173℃ ＩＲ（KBr）：3250，1760，1720，1600，1520cm-1 ＮＭＲ（DMSO-d6）：δ＝4.48（d,1H,J＝16.4Hz），
4.59（d,1H,J＝16.4Hz），5.06（d,1H,J＝8.4Hz），7.0
6（d,1H,J＝8.4Hz），7.58（d,2H,J＝8.8Hz），8.19
（d,2H,J＝8.8Hz），10.99（s,1H） ＭＳ（m/z）：251（Ｍ＋），151，136，106，105，9
0，89，78，77，63，44，30 ５−ヒドロキシ−１−（２−メチルベンジル）ヒダント
イン （化合物１０） 収率：34.8％ 融点：167.5−169℃ ＩＲ（KBr）：3420，3250，3150，3030，1760，172
0，1695cm-1 ＮＭＲ（DMSO-d6）：δ＝2.27（s,3H)，4.22（d,1H,J
＝16.0Hz），4.56（d,1H,J＝16.0Hz），4.87（d,1H,J＝
8.4Hz），6.98（d,1H,J＝8.4Hz），7.13-7.21（m,4
H），10.92（s,1H) ＭＳ（m/z）：220（Ｍ＋），202，146，120，105，10
4，91，77，65，51，39 ５−ヒドロキシ−１−（３−メチルベンジル）ヒダント
イン （化合物１１） 収率：45.4％ 融点：123−126℃ ＩＲ（KBr）：3250，3150，3030，1760，1695cm-1 ＮＭＲ（DMSO-d6）：δ＝2.27（s,3H)，4.17（d,1H,J
＝15.6Hz），4.53（d,1H,J＝15.6Hz），4.93（d,1H,J＝
8.8Hz），7.00（d,1H,J＝8.8Hz），7.07（t,3H,J＝7.6H
z），7.20（t,1H,J＝7.6Hz），10.89（s,1H) ＭＳ（m/z）：220（Ｍ＋），146，120，105，91，7
7，65，63，51，44，39，29 ５−ヒドロキシ−１−（４−メチルベンジル）ヒダント
イン （化合物１２） 収率：42.4％ 融点：172.5−174℃ ＩＲ（KBr）：3400，3250，1780，1705cm-1 ＮＭＲ（DMSO-d6）：δ＝2.27（s,3H)，4.15（d,1H,J
＝15.6Hz），4.53（d,1H,J＝15.6Hz），4.90（d,1H,J＝
8.4Hz），7.01（d,1H,J＝8.4Hz），7.12（t,2H,J＝8.4H
z），7.16（d,2H,J＝8.4Hz），10.88（s,1H) ＭＳ（m/z）：220（Ｍ＋），146，120，105，91，7
7，65，63，51，44，39，29 ５−ヒドロキシ−１−（２−メトキシベンジル）ヒダン
トイン （化合物１３） 収率：34.9％ 融点：127−130℃ ＩＲ（KBr）：3400，3250，3150，3030，1760，1695c
m-1 ＮＭＲ（DMSO-d6）：δ＝3.79（s,3H），4.29（d,1H,
J＝16.4Hz），4.43（d,1H,J＝16.4Hz），4.96（d,1H,J
＝8.4Hz），6.87-7.26（m,5H），10.87（s,1H) ＭＳ（m/z）：236（Ｍ＋），218，162，147，136，12
1，91，78，77，65，51，39 ５−ヒドロキシ−１−（３−メトキシベンジル）ヒダン
トイン （化合物１４） 収率：54.4％ 融点：100−102℃ ＩＲ（KBr）：3310，3200，3040，1760，1720，169
5，1580cm-1 ＮＭＲ（DMSO-d6）：δ＝3.73（s,3H），4.20（d,1H,
J＝16.0Hz），4.52（d,1H,J＝16.0Hz），4.95（d,1H,J
＝8.4Hz），6.81-6.86（m,3H），7.02（d,1H,J＝8.4H
z），7.21-7.25（m,1H），10.89（s,1H) ＭＳ（m/z）：236（Ｍ＋），218，162，147，136，12
1，107，91，78，77，63，51，50，39 ５−ヒドロキシ−１−（４−メトキシベンジル）ヒダン
トイン （化合物１５） 収率：28.8％ 融点：111−115℃ ＩＲ（KBr）：3420，3260，3050，1765，1700cm-1 ＮＭＲ（DMSO-d6）：δ＝3.72（s,3H），4.12（d,1H,
J＝15.2Hz），4.51（d,1H,J＝15.2Hz），4.89（d,1H,J
＝8.4Hz），6.88（d,2H,J＝8.4Hz），7.00（d,1H,J＝8.
4Hz），7.21（d,2H,J＝8.4Hz），10.87（s,1H) ＭＳ（m/z）：236（Ｍ＋），162，136，121，78，7
7，63，51，39，29，15 ５−ヒドロキシ−１−（3,4−ジメトキシベンジル）ヒ
ダントイン （化合物１６） 収率：37.6％ 融点：146−148℃ ＩＲ（KBr）：3400，3240，1775，1735，1590cm-1 ＮＭＲ（DMSO-d6）：δ＝3.71（s,3H），3.72（s,3
H），4.11（d,1H,J＝15.4Hz），4.51（d,1H,J＝15.4H
z），4.91（d,1H,J＝8.4Hz），6.79（dd,1H,J1＝1.6H
z，J2＝8.4Hz），6.86（d,1H,J＝1.6Hz），6.88（d,1H,
J＝8.4Hz），6.99（d,1H,J＝8.4Hz），10.86（s,1H) ＭＳ（m/z）：266（Ｍ＋），192，166，151，137，12
1，107，77，65，51，39，29，15 ５−ヒドロキシ−１−（3,4−ジクロロベンジル）ヒダ
ントイン （化合物１７） 収率：29.1％ 融点：155−160℃ ＩＲ（KBr）：3400，3200，3050，1780，1720cm-1 ＮＭＲ（DMSO-d6）：δ＝4.32（d,1H,J＝16.4Hz），
4.46（d,1H,J＝16.4Hz），5.03（d,1H,J＝8.4Hz），7.0
1（d,1H,J＝8.4Hz），7.30（dd,1H,J1＝2.0Hz，J2＝8.4
Hz），7.57（d,1H,J＝2.0Hz），7.58（d,1H,J＝8.4H
z），10.93（s,1H) ＭＳ（m/z）：274（Ｍ＋），200，174，159，123，8
9，63，44，29 （作用） 次に、本発明化合物の薬理作用について述べる。5-Hydroxy-1- (2-fluorobenzyl) hydantoin (Compound 2) Yield: 47.6% Melting point: 141.5-143.5 ° C IR (KBr): 3400,3320,3050,17801710,1580cm
-1 NMR (DMSO-d 6) : δ = 4.36 (d, 1H, J = 16.0Hz),
4.54 (d, 1H, J = 16.0Hz), 4.97 (d, 1H, J = 8.8Hz), 7.0
1 (d, 1H, J = 8.8Hz), 7.14-7.40 (m, 4H), 10.93 (s, 1
H) MS (m / z): 224 (M + ), 150, 124, 109, 95, 8
3,72,57,44,29 5-Hydroxy-1- (3-fluorobenzyl) hydantoin (Compound 3) Yield: 49.1% Melting point: 128-129 ° C IR (KBr): 3400, 3200, 1760, 1705 , 1590 cm -1 NMR (DMSO-d 6 ): δ = 4.30 (d, 1H, J = 16.4 Hz),
4.52 (d, 1H, J = 16.4Hz), 5.01 (d, 1H, J = 8.8Hz), 7.0
2 (d, 1H, J = 8.8Hz), 7.05-7.39 (m, 4H), 10.92 (s, 1
H) MS (m / z): 224 (M + ), 150, 124, 109, 95, 8
3,72,57,44,29 5-Hydroxy-1- (4-fluorobenzyl) hydantoin (Compound 4) Yield: 50.6% Melting point: 181-282 ° C IR (KBr): 3400, 3280, 1780, 1710 , 1600 cm -1 NMR (DMSO-d 6 ): δ = 4.24 (d, 1H, J = 15.6 Hz),
4.51 (d, 1H, J = 15.6Hz), 4.96 (d, 1H, J = 8.8Hz), 7.0
1 (d, 1H, J = 8.8Hz), 7.12-7.35 (m, 4H), 10.90 (s, 1
H) MS (m / z): 224 (M + ), 150, 124, 109, 95, 8
3,72,57,44,29 5-Hydroxy-1- (4-chlorobenzyl) hydantoin (Compound 5) Yield: 36.4% Melting point: 130-133 ° C IR (KBr): 3240, 3150, 3030, 1760, 1700 cm -1 NMR (DMSO-d 6 ): δ = 4.42 (d, 1H, J = 16.4Hz),
4.53 (d, 1H, J = 16.4Hz), 5.02 (d, 1H, J = 8.8Hz), 7.0
2 (d, 1H, J = 8.8Hz), 7.30-7.46 (m, 4H), 10.98 (s, 1
H) MS (m / z): 224 (M + ), 205, 166, 140, 125, 9
9,89,77,72,44,29 5-Hydroxy-1- (4-chlorobenzyl) hydantoin (Compound 6) Yield: 39.5% Melting point: 150.5-152 ° C IR (KBr): 3460, 3160, 3030, 1780, 1705 cm -1 NMR (DMSO-d 6 ): δ = 4.26 (d, 1H, J = 16.0Hz),
4.49 (d, 1H, J = 16.0Hz), 4.97 (d, 1H, J = 8.4Hz), 7.0
2 (d, 1H, J = 8.4Hz), 7.32 (d, 2H, J = 8.4Hz), 7.38 (d
d, 2H, J 1 = 2.0Hz, J 2 = 8.4Hz), 10.91 (s, 1H) MS (m / z): 240 (M + ), 166, 140, 125, 111, 9
9,89,77,72,63,44,29 5-Hydroxy-1- (4-bromobenzyl) hydantoin (Compound 7) Yield: 39.2% Melting point: 168.5-169.5 ° C IR (KBr): 3470, 3160, 3030, 1780, 1705, 1590c
m -1 NMR (DMSO-d 6 ): δ = 4.24 (d, 1H, J = 16.0Hz),
4.47 (d, 1H, J = 16.0Hz), 4.98 (d, 1H, J = 8.4Hz), 7.0
1 (d, 1H, J = 8.4Hz), 7.26 (d, 2H, J = 8.4Hz), 7.51 (d
t, 2H, J 1 = 2.0Hz, J 2 = 8.4Hz), 10.91 (s, 1H) MS (m / z): 284 (M + ), 210, 184, 169, 90, 8
9,77,72,63,50,39,29 5-Hydroxy-1- (3-nitrobenzyl) hydantoin (Compound 8) Yield: 47.8% Melting point: 161-163 ° C IR (KBr): 3375, 3200, 3080, 1755, 1720, 1540c
m -1 NMR (DMSO-d 6 ): δ = 4.48 (d, 1H, J = 15.6Hz),
4.58 (d, 1H, J = 15.6Hz), 5.06 (d, 1H, J = 8.8Hz), 7.0
5 (d, 1H, J = 8.8Hz), 7.63 (dd, 1H, J 1 = 8.0Hz, J 2 = 8.0H
z), 7.77 (d, 1H, J = 8.0Hz), 8.12 (d, 1H, J = 8.0H)
z), 8.17 (s, 1H), 10.96 (s, 1H) MS (m / z): 251 (M + ), 234, 163, 161, 151, 13
6,105,90,89,77,63,51,50,39,30 5-Hydroxy-1- (4-nitrobenzyl) hydantoin (Compound 9) Yield: 51.0% Melting point: 171-173 ° C IR (KBr ): 3250, 1760, 1720, 1600, 1520 cm -1 NMR (DMSO-d 6 ): δ = 4.48 (d, 1H, J = 16.4Hz),
4.59 (d, 1H, J = 16.4Hz), 5.06 (d, 1H, J = 8.4Hz), 7.0
6 (d, 1H, J = 8.4Hz), 7.58 (d, 2H, J = 8.8Hz), 8.19
(D, 2H, J = 8.8Hz), 10.99 (s, 1H) MS (m / z): 251 (M + ), 151, 136, 106, 105, 9
0,89,78,77,63,44,30 5-Hydroxy-1- (2-methylbenzyl) hydantoin (Compound 10) Yield: 34.8% Melting point: 167.5-169 ° C IR (KBr): 3420, 3250, 3150, 3030, 1760, 172
0,1695 cm -1 NMR (DMSO-d 6 ): δ = 2.27 (s, 3H), 4.22 (d, 1H, J
= 16.0Hz), 4.56 (d, 1H, J = 16.0Hz), 4.87 (d, 1H, J =
8.4Hz), 6.98 (d, 1H, J = 8.4Hz), 7.13-7.21 (m, 4
H), 10.92 (s, 1H) MS (m / z): 220 (M + ), 202, 146, 120, 105, 10
4,91,77,65,51,39 5-Hydroxy-1- (3-methylbenzyl) hydantoin (Compound 11) Yield: 45.4% Melting point: 123-126 ° C IR (KBr): 3250, 3150, 3030, 1760, 1695 cm -1 NMR (DMSO-d 6 ): δ = 2.27 (s, 3H), 4.17 (d, 1H, J
= 15.6Hz), 4.53 (d, 1H, J = 15.6Hz), 4.93 (d, 1H, J =
8.8Hz), 7.00 (d, 1H, J = 8.8Hz), 7.07 (t, 3H, J = 7.6H
z), 7.20 (t, 1H, J = 7.6Hz), 10.89 (s, 1H) MS (m / z): 220 (M + ), 146, 120, 105, 91, 7
7,65,63,51,44,39,29 5-Hydroxy-1- (4-methylbenzyl) hydantoin (Compound 12) Yield: 42.4% Melting point: 172.5-174 ° C IR (KBr): 3400,3250, 1780, 1705 cm -1 NMR (DMSO-d 6 ): δ = 2.27 (s, 3H), 4.15 (d, 1H, J
= 15.6Hz), 4.53 (d, 1H, J = 15.6Hz), 4.90 (d, 1H, J =
8.4Hz), 7.01 (d, 1H, J = 8.4Hz), 7.12 (t, 2H, J = 8.4H)
z), 7.16 (d, 2H, J = 8.4Hz), 10.88 (s, 1H) MS (m / z): 220 (M + ), 146, 120, 105, 91, 7
7,65,63,51,44,39,29 5-Hydroxy-1- (2-methoxybenzyl) hydantoin (Compound 13) Yield: 34.9% Melting point: 127-130 ° C IR (KBr): 3400, 3250, 3150, 3030, 1760, 1695c
m -1 NMR (DMSO-d 6 ): δ = 3.79 (s, 3H), 4.29 (d, 1H,
J = 16.4Hz), 4.43 (d, 1H, J = 16.4Hz), 4.96 (d, 1H, J
= 8.4Hz), 6.87-7.26 (m, 5H), 10.87 (s, 1H) MS (m / z): 236 (M + ), 218, 162, 147, 136, 12
1,91,78,77,65,51,39 5-Hydroxy-1- (3-methoxybenzyl) hydantoin (Compound 14) Yield: 54.4% Melting point: 100-102 ° C IR (KBr): 3310,3200, 3040, 1760, 1720, 169
5,1580 cm -1 NMR (DMSO-d 6 ): δ = 3.73 (s, 3H), 4.20 (d, 1H,
J = 16.0Hz), 4.52 (d, 1H, J = 16.0Hz), 4.95 (d, 1H, J
= 8.4Hz), 6.81-6.86 (m, 3H), 7.02 (d, 1H, J = 8.4H
z), 7.21-7.25 (m, 1H), 10.89 (s, 1H) MS (m / z): 236 (M + ), 218, 162, 147, 136, 12
1,107,91,78,77,63,51,50,39 5-Hydroxy-1- (4-methoxybenzyl) hydantoin (Compound 15) Yield: 28.8% Melting point: 111-115 ° C IR (KBr): 3420, 3260, 3050, 1765, 1700 cm -1 NMR (DMSO-d 6 ): δ = 3.72 (s, 3H), 4.12 (d, 1H,
J = 15.2Hz), 4.51 (d, 1H, J = 15.2Hz), 4.89 (d, 1H, J
= 8.4Hz), 6.88 (d, 2H, J = 8.4Hz), 7.00 (d, 1H, J = 8.
4Hz), 7.21 (d, 2H, J = 8.4Hz), 10.87 (s, 1H) MS (m / z): 236 (M + ), 162, 136, 121, 78, 7
7,63,51,39,29,15 5-Hydroxy-1- (3,4-dimethoxybenzyl) hydantoin (Compound 16) Yield: 37.6% Melting point: 146-148 ° C IR (KBr): 3400, 3240, 1775, 1735, 1590 cm -1 NMR (DMSO-d 6 ): δ = 3.71 (s, 3H), 3.72 (s, 3
H), 4.11 (d, 1H, J = 15.4Hz), 4.51 (d, 1H, J = 15.4H)
z), 4.91 (d, 1H, J = 8.4Hz), 6.79 (dd, 1H, J 1 = 1.6H
z, J 2 = 8.4Hz), 6.86 (d, 1H, J = 1.6Hz), 6.88 (d, 1H,
J = 8.4Hz), 6.99 (d, 1H, J = 8.4Hz), 10.86 (s, 1H) MS (m / z): 266 (M + ), 192,166,151,137,12
1,107,77,65,51,39,29,15 5-Hydroxy-1- (3,4-dichlorobenzyl) hydantoin (Compound 17) Yield: 29.1% Melting point: 155-160 ° C IR (KBr): 3400, 3200, 3050, 1780, 1720cm -1 NMR (DMSO-d 6 ): δ = 4.32 (d, 1H, J = 16.4Hz),
4.46 (d, 1H, J = 16.4Hz), 5.03 (d, 1H, J = 8.4Hz), 7.0
1 (d, 1H, J = 8.4Hz), 7.30 (dd, 1H, J 1 = 2.0Hz, J 2 = 8.4
Hz), 7.57 (d, 1H, J = 2.0Hz), 7.58 (d, 1H, J = 8.4H
z), 10.93 (s, 1H) MS (m / z): 274 (M + ), 200, 174, 159, 123, 8
9, 63, 44, 29 (Action) Next, the pharmacological action of the compound of the present invention will be described.
(1)脂質低下作用 一群８匹のWister系雄性ラット（体重185ｇ前後）を20
時間絶食後、0.5％ＣＭＣ−Ｎａ水溶液にて溶解或いは
懸濁した100mgの被検薬を経口投与した。２時間後ペン
トバルビタール麻酔下で開腹し、腹部大静脈より採血し
た。得られた血液を30分間放置して完全に凝固させた後
遠心分離して血清を採取した。得られた血清を用いてＧ
ＰＯ−ｐ−クロルフェノール発色法〔Richard W.Spayd
et al.,Clinacal Chemstry,24,1343(1978)〕によりトリ
グリセライド（ＴＧ）を、Acyl CoA Synthetase-Acyl C
oA Oxidase法〔Shimizu S. et al.,Biochem.Biophys.Re
s.Commun.,91,108(1979)〕により遊離脂肪酸（ＦＦＡ）
を、また酵素法〔Takayama M.et al.,Clinica Chimica
Acta,79,93(1977)〕によりリン脂質（ＰＬ）をそれぞれ
測定した。(1) Lipid-lowering effect A group of 8 Wistar male rats (body weight: around 185 g)
After fasting for 100 hours, 100 mg of the test drug dissolved or suspended in a 0.5% CMC-Na aqueous solution was orally administered. Two hours later, the abdomen was opened under pentobarbital anesthesia, and blood was collected from the abdominal vena cava. The obtained blood was left to stand for 30 minutes for complete coagulation and then centrifuged to collect serum. G using the obtained serum
PO-p-chlorophenol color development method [Richard W. Spayd
et al., Clinacal Chemstry, 24 , 1343 (1978)], triglyceride (TG), Acyl CoA Synthetase-Acyl C
oA Oxidase method (Shimizu S. et al., Biochem. Biophys. Re
s.Commun., 91 , 108 (1979)] free fatty acid (FFA)
By the enzymatic method [Takayama M. et al., Clinica Chimica
Acta, 79 , 93 (1977)], and phospholipid (PL) was measured.
結果の一例を表１に示す。An example of the results is shown in Table 1.
(2)急性毒性 一群１０匹のddy系雄性マウスを用いて、被検物質投与
後７日間の死亡率よりリッチフィールド−ウィルコキソ
ン法を用いてＬＤ50を算出した。 (2) using the acute toxicity group ten ddy male mice, Litchfield than mortality 7 days after the administration the test substance - was calculated Wilcoxon method LD 50 using.
その結果、前記実施例に示した本発明化合物を経口、静
脈内、腹腔内、皮下投与したとき、いずれの場合にもＬ
Ｄ50は、2,000mg／kg以上であった。また投与時の副作
用や、試験終了後の剖検における内蔵各器官の異常は特
に観察されなかった。As a result, when the compound of the present invention shown in the above Example was orally, intravenously, intraperitoneally or subcutaneously administered, L
The D 50 was 2,000 mg / kg or more. In addition, no side effects at the time of administration and no abnormalities in the internal organs at necropsy after the test were observed.
（発明の効果） 上記薬理試験の結果より明らかなように、本発明ヒダン
トイン誘導体はトリグリセライド、遊離脂肪酸、リン脂
質等の血中脂質を有意に低下させ、優れた脂質低下作用
を示す。(Effect of the Invention) As is clear from the results of the above-mentioned pharmacological tests, the hydantoin derivative of the present invention significantly reduces blood lipids such as triglyceride, free fatty acids, and phospholipids, and exhibits an excellent lipid-lowering action.
従って、本発明化合物は動脈硬化症、ネフローゼ、高血
圧症、糖尿病、肥満、その他各種疾患に伴う高脂血症の
治療並びに予防に有用な脂質低下剤である。本発明化合
物は低毒性で副作用も少なく経口投与可能なため、完全
に長期的な使用ができ、特に慢性的な疾患を治療するの
に有利である。Therefore, the compound of the present invention is a lipid-lowering agent useful for the treatment and prevention of arteriosclerosis, nephrosis, hypertension, diabetes, obesity and other hyperlipidemia associated with various diseases. Since the compound of the present invention has low toxicity and few side effects and can be orally administered, it can be used completely for a long time, and is particularly advantageous for treating chronic diseases.
本発明化合物は、適当な医薬用の担体若しくは希釈剤と
組み合わせて医薬とすることができ、通常の如何なる方
法によっても製剤化でき、経口又は非経口投与するため
の固体、半固体、液体又はエアゾールの剤形に処方する
ことができる。The compound of the present invention can be made into a medicine by combining with a suitable pharmaceutical carrier or diluent, and can be formulated by any ordinary method. It can be solid, semisolid, liquid or aerosol for oral or parenteral administration. Can be formulated into a dosage form of
処方にあたっては、本発明化合物をその薬理学的に許容
しうる塩の形で用いてもよく、本発明化合物を単独で若
しくは適宜組み合わせて用いることができ、又、他の医
薬活性成分との配合剤としてもよい。In the prescription, the compound of the present invention may be used in the form of its pharmacologically acceptable salt, and the compound of the present invention can be used alone or in an appropriate combination, and can be mixed with other pharmaceutically active ingredients. It may be used as an agent.
経口投与製剤には、そのまま或いは適当な添加剤、例え
ば乳糖、マンニット、トウモロコシデンプン、バレイシ
ョデンプン等の慣用の賦形剤と共に、結晶セルロース、
セルロース誘導体、アラビアゴム、トウモロコシデンプ
ン、ゼラチン等の結合剤、トウモロコシデンプン、バレ
イショデンプン、カルボキシメチルセルロースナトリウ
ム等の崩壊剤、タルク、ステアリン酸マグネシウム等の
滑沢剤、その他増量剤、湿潤化剤、緩衝剤、保存剤、香
料等を適宜組み合わせて錠剤、散剤、顆粒剤或いはカプ
セル剤とすることができる。In the preparation for oral administration, crystalline cellulose, as it is or together with suitable additives, for example, conventional excipients such as lactose, mannitol, corn starch and potato starch,
Cellulose derivatives, gum arabic, corn starch, gelatin and other binders, corn starch, potato starch, sodium carboxymethyl cellulose and other disintegrants, talc, magnesium stearate and other lubricants, other extenders, wetting agents, buffers Tablets, powders, granules or capsules can be prepared by appropriately combining a preservative, a fragrance and the like.
非経口投与用には、注射剤として水性溶剤又は非水性溶
剤、例えば注射用蒸溜水、生理食塩水、リンゲル液、植
物油、合成樹脂酸グリセリド、高級脂肪酸エステル、プ
ロピレングリコール等を用いて溶液、懸濁液若しくは乳
化液とすることができ、適宜防腐剤、安定化剤、緩衝化
剤、溶解補助剤等を加えることができる。又、用時溶解
して用いるための注射用乾燥物としてもよい。For parenteral administration, an aqueous solution or a non-aqueous solvent as an injection, for example, distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic resin acid glyceride, higher fatty acid ester, propylene glycol solution, suspension is used. It can be a liquid or an emulsion, and an antiseptic, a stabilizer, a buffering agent, a solubilizing agent and the like can be added as appropriate. Further, it may be a dried product for injection to be dissolved before use.
又、本発明化合物は軟膏基剤、例えばワセリン、パラフ
ィン、プラスチベース、単軟膏、単鉛軟膏、親水軟膏、
親水ワセリン、親水プラスチベース等と組み合わせて軟
膏とすることができ、或いは、各種基剤、例えば乳剤性
基剤又は水溶性基剤と混和して坐剤を製造することがで
きる。Further, the compound of the present invention is an ointment base such as petrolatum, paraffin, plastibase, single ointment, single lead ointment, hydrophilic ointment,
It can be combined with hydrophilic petrolatum, hydrophilic plastibase or the like to give an ointment, or can be mixed with various bases such as an emulsion base or a water-soluble base to produce a suppository.
吸入剤、エアゾール剤として使用するには、本発明化合
物を液体又は微小粉体の形で、気体又は液体噴射剤と共
に、且つ所望により湿潤剤又は分散剤のような通常の補
薬と共にエアゾール容器内に充填する。本発明化合物
は、ネブライザー又はアトマイザのような非加圧型の剤
形にしてもよい。For use as an inhalant or aerosol, the compound of the invention is in the form of a liquid or fine powder in an aerosol container together with a gas or a liquid propellant and, if desired, a conventional auxiliary such as a wetting agent or a dispersant. To fill. The compound of the present invention may be in a non-pressurized dosage form such as a nebulizer or an atomizer.
パップ剤としては、ハッカ油、濃グリセリン、カオリン
等と混合して製造することができる。As a poultice, it can be produced by mixing with peppermint oil, concentrated glycerin, kaolin and the like.
本発明化合物の望ましい投与量は、投与対象、剤形、投
与方法、投与期間等によって変わるが、所望の効果を得
るには、一般に成人に対して一日に本発明化合物を１乃
至1,000mg、好ましくは５乃至600mg経口投与することが
でき、又、本発明化合物を適当量含有する単位製剤を一
日１乃至数単位投与することができる。Although the desirable dose of the compound of the present invention varies depending on the administration subject, dosage form, administration method, administration period, etc., in order to obtain the desired effect, generally 1 to 1,000 mg of the compound of the present invention per day for an adult, Preferably, 5 to 600 mg can be orally administered, and a unit preparation containing an appropriate amount of the compound of the present invention can be administered 1 to several units per day.
非経口投与（例えば注射剤）の場合、一日投与量は、前
記投与量の３乃至10分の１程度の用量レベルのものが好
ましい。In the case of parenteral administration (eg, injection), the daily dose is preferably at a dose level of about 3 to 1/10 of the above dose.
以下に本発明発明化合物を有効成分として含有する医薬
組成物の処方例を示す。Formulation examples of pharmaceutical compositions containing the compound of the present invention as an active ingredient are shown below.
処方例１．（錠剤） 処方例２．（カプセル剤） 処方例３．（注射剤） 処方例５．（座剤） 処方例４．（軟膏剤） Prescription example 1. (tablet) Prescription example 2. (Capsule) Prescription example 3. (Injection) Prescription example 5. (Suppository) Prescription example 4. (Ointment)
Claims (2)
導体及びその薬学的に許容しうる塩。 （式中、Ｒ１及びＲ２は同一若しくは異なって水素、ハ
ロゲン、ニトロ基、低級アルキル基又は低級アルコキシ
基を表す。但しＲ１が水素且つＲ２が３−メトキシ基で
ある場合を除く。）1. A hydantoin derivative represented by the general formula (I ′) and a pharmaceutically acceptable salt thereof. (In the formula, R 1 and R 2 are the same or different and each represent hydrogen, halogen, a nitro group, a lower alkyl group or a lower alkoxy group, provided that R 1 is hydrogen and R 2 is a 3-methoxy group. )
体及びその薬学的に許容しうる塩の少なくとも一種を有
効成分として含有する脂質低下剤。 （式中、Ｒ１及びＲ２は同一若しくは異なって水素、ハ
ロゲン、ニトロ基、低級アルキル基又は低級アルコキシ
基を表す。）2. A hypolipidemic agent containing as an active ingredient at least one of a hydantoin derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof. (In the formula, R 1 and R 2 are the same or different and each represents hydrogen, halogen, a nitro group, a lower alkyl group or a lower alkoxy group.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60287097A JPH0662584B2 (en) | 1985-12-19 | 1985-12-19 | Novel hydantoin derivative and lipid lowering agent containing the compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60287097A JPH0662584B2 (en) | 1985-12-19 | 1985-12-19 | Novel hydantoin derivative and lipid lowering agent containing the compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62145068A JPS62145068A (en) | 1987-06-29 |
| JPH0662584B2 true JPH0662584B2 (en) | 1994-08-17 |
Family
ID=17713016
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60287097A Expired - Lifetime JPH0662584B2 (en) | 1985-12-19 | 1985-12-19 | Novel hydantoin derivative and lipid lowering agent containing the compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0662584B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19934231B4 (en) * | 1999-07-21 | 2004-02-19 | Bayer Ag | Process for the preparation of 1-substituted 5-hydroxy-imidazoline-2,4-diones and 1-substituted 5-alkoxy-imidazoline-2,4-diones |
| EP3639821B1 (en) | 2017-06-13 | 2024-08-28 | National Cancer Center | Carcinogenesis inhibitor |
-
1985
- 1985-12-19 JP JP60287097A patent/JPH0662584B2/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| J.ORG.CHEM=1984 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62145068A (en) | 1987-06-29 |
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